Photodynamic therapy (PDT) is an experimental cancer treatment that is based on the administration of tumor-localizing photosensitizer and subsequent excitation with visible light to produce tumor destruction. Animal studies using Photofri (porfimer sodium) have described the release of vasoactive eicosanoids, arteriole constriction and platelet aggregation which lead to blood flow stasis and are critical for tumor destruction. Other photosensitizers cause damage through variations of this mechanism. Agents such as NPe6 cause blood flow stasis, but do not without vessel constriction. Studies using disulfonated zinc phthalocanine have demonstrated tumor destruction without vascular stasis, suggesting that this photosensitizer does not interact with the vasculature in the same manner as the other photosensitizers. A complete understanding how these agents cause vessel damage and evoke tumor destruction is necessary if they are to be successfully targeted and used in PDT. The confirmation of structure/activity relationships of photosensitizers will also give a better responses that PDT with single agents alone. Drugs that cause direct cell damage will be combined with agents that produce vascular stasis to increase the efficacy of treatment. Our experimental plan is to examine in detail the effects of PDT treatment on blood and vascular components using three different photosensitizers: Photofrin, NPe6 and zinc disulfonated phtalocyanine. We will monitor exposure of basement membrane proteins in gaps between endothelial cells, examine the role of platelet aggregation in blood flow stasis, and detail PMN adhesion to the endothelium cells, examine the role of platelet aggregation in blood flow stasis, and detail PMN adhesion to the endothelium in both normal and tumor microvasculature during and after PDT. To further characterize the mechanism of the vascular response to PDT, we will employ specific inhibitors of the cyclooxygenase and/or ipoxygenase pathways of eicosanoid synthesis and reevaluate the above vascular measurements. The specific contribution of platelets and PMNs in the vascular response to PDT will be investigated by treating animals made thrombocytopenic or leukopenic before therapy. We will also examine the role of platelets, PMNs and arachidonic acid metabolites released from tumor treated on the hind limb of rats during and after PDT on damage to the pulmonary microcirculation. High systemic levels of arachidonic acid metabolites, platelet aggregates and activated PMNs may cause damage to the lung. Previous studies have shown animal death as a result of lung damage after PDT of distant sites. We will also characterize the ability of photosensitizers to induce direct tumor cytotoxicity. We will combine these data with the results from the vascular studies to determine the roles of direct vs. indirect damage for each of the photosensitizers under study. These data will be used to combine drugs with overlapping mechanisms of damage for PDT. Photosensitizers which damage tumor cells directly will be combined with agents which cause vascular stasis to increase the efficacy of tumor destruction.